The present invention relates to therapeutic combinations comprising an effective amount of camptothecin, or a camptothecin derivative such as irinotecan (CPT-11), with an effective amount of an alkylating agent for the treatment of cancer.
More specifically, the invention relates to anticancer treatments with associations of camptothecin derivatives such as irinotecan (CPT-11, CAMPTOSAR(copyright)), topotecan, 9-aminocamptothecin, or 9-nitrocamptothecin, and alkylating agents. Such alkylating agents include, inter alia, melphalan (alkeran, L-3-{para-[Bis(2-chloroethyl)amino]phenyl}alanine, CB 3025, phenylalanine mustard, L-Sarcolysine, SK-15673), dacarbazine (DTIC-Dome(copyright), DTIC, dimethyl triazeno imidazole carboxamide; 5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide, 9CI, DIC), and cyclophosphamide (CPA, CYTOXAN(copyright), NEOSAR(copyright)).
European patent EP 137,145, specifically incorporated by reference herein, describes camptothecin derivatives of the formula: 
in which, in particular, R1 is hydrogen, halogen or alkyl; X is a chlorine atom, or NR2R3, in which R2 and R3, which may be identical or different, may represent a hydrogen atom, an optionally substituted alkyl radical, a carbocycle or a heterocycle which are optionally substituted, or alkyl radicals (optionally substituted) forming, with the nitrogen atom to which they are attached, a heterocycle optionally containing another heteroatom chosen from O, S, and/or NR4, wherein R4 is a hydrogen atom or an alkyl radical; and in which the group Xxe2x80x94COxe2x80x94Oxe2x80x94 is located on ring A in position 9, 10, or 11.
These camptothecin derivatives are anticancer agents which inhibit topoisomerase I, among which irinotecan, in which Xxe2x80x94COxe2x80x94Oxe2x80x94 is [4-(1-piperidino-1-piperidino]carbonyloxy, is an active principle which is particularly effective in treatment of solid tumors. Camptothecin and camptothecin derivatives such as irinotecan are cytotoxic alkaloids which possesses strong anti-tumor activities. Irinotecan shows clinical activity against colon, gastric, ovarian, and small cell lung cancers, as well as non-Hodgkin""s lymphoma (Bissery, M. et al., Anti Cancer Drugs, 7:166-174 (1996)).
The European patent application EP 74,256 also describes other camptothecin derivatives which are also mentioned as anticancer agents, in particular, derivatives of a structure analogous to the structure given above and in which Xxe2x80x94COxe2x80x94Oxe2x80x94 is replaced with a radical xe2x80x94Xxe2x80x2Rxe2x80x2 for which Xxe2x80x2 is O or S, and Rxe2x80x2 is a hydrogen atom or an alkyl or acyl radical.
Other camptothecin derivatives have also been described, for example, in the following publications, patents, or patent applications: EP 56,692; EP 88,642; EP 296,612; EP 321,122; EP 325,247; EP 540,099; EP 737,686; WO 90/03169; WO 96/37496; WO 96/38146; WO 96/38449; WO 97/00876; U.S. Pat. No. 7,104,894; JP 57 116,015; JP 57 116,074; JP 59 005,188; JP 60 019,790; JP 01 249,777; JP 01 246,287; and JP 91 12070; Canc. Res., 38 (1997) Abstr. 1526 or 95 (San Diego, April 12-16); Canc. Res., 55(3):603-609 (1995); or AFMC Int. Med. Chem. Symp. (1997) Abstr. PB-55 (Seoul, Korea; July 27-August 1).
Camptothecin derivatives are usually administered by injection, more particularly intravenously in the form of a sterile solution or an emulsion. Camptothecin derivatives, however, can also be administered orally, in the form of solid or liquid compositions.
However, while camptothecin and camptothecin derivatives are considered to be some of the most powerful substances possessing anti-tumor activity, for example in colorectal cancers, the use of these compounds can be improved by association with other antitumor agents.
Among such antitumor agents are alkylating agents which have antineoplastic activity. Such alkylating agents include inter alia melphalan (alkeran, L-3-{para-[Bis(2-chloroethyl) amino]phenyl}alanine, CB 3025, phenylalanine mustard, L-Sarcolysine, SK-15673), dacarbazine (DTIC-Dome(copyright), DTIC, dimethyl triazeno imidazole carboxamide; 5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide, 9CI, DIC), and cyclophosphamide (CPA, CYTOXAN(copyright), NEOSAR(copyright)).
It has been discovered that combinations of camptothecin and an alkylating agent such as cyclophosphamide significantly reduce the development of tumor volume compared to the development of tumor volume from the administration of each compound alone, as predicted from administration to tumor-infected mammals.
The combination of CPT-11 and cyclophosphamide has been studied in Japan (Furuta, Tomio et al., Cancer Chemotherapy, 18(3): 393-402 (1991)). In that study, however, the evaluation of the combination was only conducted on L1210 mouse leukemia, not on solid tumors. The route of administration of CPT-11 and cyclophosphamide was via the abdominal cavity, that is, the drugs were administered intraperitoneally and not orally or intravenously. Furthermore, Furuta et al. did not evaluate the effect of the highest non-toxic dose of either camptothecin or cyclophosphamide as single agents. Without such a determination, it is not possible to determine the synergistic effect of the CPT-11/cyclophosphamide combination.
It has now been found that the combination of CPT-11 and cyclophosphamide is more active at a lower dose than the highest non-toxic dose of each single agent for the treatment of cancer, including, for example, mammary adenocarcinoma. PATENT
The efficacy of a combination may be demonstrated by determination of therapeutic synergy. A combination manifests therapeutic synergy if it is therapeutically superior to one or other of the constituents used at its optimum dose (T. H. Corbett et al., Cancer Treatment Reports, 66: 1187 (1982)).
The efficacy of a combination may also been demonstrated by comparison of the maximum tolerated dose of the combination with the maximum tolerated dose of each of the separate constituents in the study in question. This efficacy may be quantified, for example by the log10 cell kill, which is determined by the following formula:
log10 cell kill=T-C(days)/3.32xc3x97Td
in which T-C represents the time taken for the cells to grow, which is the mean time in days for the tumors of the treated group (T) to reach a predetermined value (1 g for example) and the tumors of the control group (C) to reach the same value, and Td represents the time in days needed for the volume of the tumor in the control group to double (T. H. Corbett et al., Cancer, 40: 2660-2680 (1977); F. M. Schabel et al., Cancer Drug Development, Part B, Methods in Cancer Research, 17: 3-51, New York, Academic Press Inc. (1979)). A product is considered to be active if the log10 cell kill is greater than or equal to 0.7. A product is considered to be very active if the log10 cell kill is greater than 2.8.
It has now been found that administration of CPT-11 in combination with cyclophosphamide in the following manner with the following schedules results in a combination that is very active against cancers. Furthermore, the combination of CPT-11/cyclophosphamide is more active at a lower dose than the highest non-toxic dose of either CPT-11 or cyclophosphamide alone.
The products may be administered simultaneously, semi-simultaneously, separately, or spaced out over a period of time so as to obtain the maximum efficacy of the combination. As a result, the invention is not limited to the compositions obtained by the physical association of the drugs, but also includes those which permit separate administration, either simultaneously, semi-simultaneously, or spaced out over a period of time.